Tabletting of a drug has advantages such as high productivity and easy handling of the resulting tablets during their transportation or upon their use. Therefore, an excipient for compression molding needs to have sufficient moldability to impart such hardness that the tablets are not worn away or destroyed during their transportation or upon their use. Tablets used as medicine are required to be uniform in drug content per tablet in order to accurately exhibit their efficacy. Therefore, when mixed powder of a drug and an excipient for compression molding is compressed into the tablets, a uniform amount of the powder should be packed into the die of a tabletting machine. Accordingly, the excipient for compression molding needs to have not only moldability but also sufficient fluidity. Moreover, the tablets as medicine should have not only the properties described above but also a short disintegration time to rapidly exhibit their efficacy after taking. With an increase of the rate of disintegration, the medicine is dissolved more rapidly in digestive fluid, so that the transfer of the medicine into blood is more rapid, resulting in easy absorption of the medicine. Therefore, the excipient for compression molding should have rapid disintegrating property in addition to moldability and fluidity.
Many active ingredient materials cannot be molded by compression and hence are tabletted by blending with an excipient for compression molding. In general, the larger the amount of the excipient for compression molding blended into the tablets, the higher the hardness of the resulting tablets. The higher the compression stress, the higher the strength of the resulting tablets. Crystalline cellulose is often used as an excipient for compression molding from the viewpoint of safety and the above-mentioned properties.
When an active ingredient and the like which are poor in moldability are tabletted in the field of medicine, an excessive compression stress is unavoidably applied attain a practical tablet hardness. The excessive compression stress on a tabletting machine accelerates the abrasion of dies and punches, and the disintegration time of the resulting tablets is increased. For example, where an amount of an active ingredient, such as a drug, to be blended is large (i.e. where the starting powder has a large specific volume) such as a Chinese orthodox medicine, is blended, or where tablets are miniturized so that the tablets are taken more easily, the problems, such as abrasion or destruction of the tablets during their transportation, are caused since the amount of an excipient blended is so remarkably limited, that desirable tablet hardness cannot be attained. Moreover, there is, for example, the problem that when the active ingredient to be used is that sensitive to striking pressure, such as an enzyme, antibiotic or the like, the active ingredient is inactivated by heat generation by striking pressure or striking pressure per se, it cannot be formulated into tablets because its content is decreased in an attempt to attain a practical hardness. In order to solve such problems, an excipient for compression molding is desired which has sufficient fluidity and disintegrating property and has a moldability higher than before, which can impart a sufficient tablet hardness even when added in a small amount, or impart a sufficient tablet hardness even at a low striking pressure.
For cellulose powder used as an excipient for medicine, compression moldability, disintegrating property and fluidity are desired to be satisfactorily high at the same time. However, since compression moldability and the other properties, i.e., disintegrating property and fluidity are contrary to each other, no previous cellulose powder that has a high moldability has exhibited excellent disintegrating property and fluidity.
Cellulose powder, crystalline cellulose and powdered cellulose have been known and used in medicinal, food and industrial applications.
JP-B-40-26274 discloses crystalline cellulose having an average polymerization degree of 15 to 375, an apparent specific volume of 1.84 to 8.92 cm3/g and a particle size of 300 μm or less. JP-B-56-2047 discloses crystalline cellulose having an average polymerization degree of 60 to 375, an apparent specific volume of 1.6 to 3.1 cm3/g, a specific volume of 1.40 cm3/g or more, a content of powder of 200-mesh size or more of 2-80 wt % and an angle of repose of 35-42°. DE2921496 discloses that cellulose powder having an average polymerization degree of 150 is produced by carrying out acid hydrolysis of a cellulose material in the form of flowable, non-fibrous and water-insoluble cellulose powder to adjust the solid content to 30-40 wt %, followed by drying on trays at 140-150° C. RU2050362 discloses a process in which in order to produce a stable gel of powdered cellulose, powdered cellulose having an average polymerization degree of 400 or less is obtained by impregnating a starting material containing cellulose with a mineral acid or an acid salt solution, and then hydrolyzing the starting material at a high temperature while stirring a starting material layer at a shear rate of 10-1,000 s−1 for 1-10 minutes. The crystalline celluloses and powdered celluloses concretely disclosed in these references, however, are disadvantageous in that the average L/D value of particles of 75 μm or less after drying, the apparent specific volume and the apparent tapping specific volume are so small that the compression moldability is low.
JP-A-63-267731 discloses cellulose powder having a certain average particle size (30 μm or less) and a specific surface area of 1.3 m2/g or more. This cellulose powder involves the following problems because it is produced through a grinding step: its moldability is insufficient because the average L/D value of particles of 75 μm or less is small; its fluidity is low because its particles are small and light; and its disintegrating property is very low because its apparent tapping specific volume is too low.
JP-A-1-272643 discloses cellulose powder having a specified crystal form (cellulose I type), a porosity for pores with a diameter of 0.1 μm or more of 20% or more, and a content of powder of 350-mesh size or more of 90% or more. JP-A-2-84401 discloses cellulose powder having a crystal form of type I, a specific surface area of 20 m2/g or more, a total volume of pores with a diameter of 0.01 μm or more of 0.3 cm3/g or more, and an average particle size of at most 100 μm. Although they have a relatively high moldability, these cellulose powders, however, are different from the cellulose powder of the present invention as the L/D value of dried powder is less than 2.0. In addition, the cellulose powders are not desirable because the nitrogen specific surface area of their particles is too large, so that their conduits are decreased during compression, resulting in low disintegrating property. Moreover, the cellulose powders disclosed in the above references are obtained by hydrolysis followed by spray drying using an organic solvent as a medium for a slurry before drying. These powders have not been put to practical use because the use of the organic solvent requires, for example, a dryer having an explosion-proof structure and a system for recovering the organic solvent and hence entails high cost.
JP-A-6-316535 discloses crystalline cellulose obtained by acid hydrolysis or alkali oxidative decomposition of a cellulosic material, which has an average polymerization degree of 100-375, an acetic acid retention of 280% or more, compression characteristics represented by Kawakita's equation wherein the constants a and b are 0.85-0.90 and 0.05-0.10, respectively, an apparent specific volume of 4.0-6.0 cm3/g, a specific volume of 2.4 cm3/g or more, a specific surface area of less than 20 m2/g, substantially no particles of 355 μm or more, and an average particle size of 30-120 μm. The crystalline cellulose powder disclosed in the above reference is described as having an excellent balance between moldability and disintegrating property. The angle of repose of the concretely disclosed crystalline cellulose powder of an example having the best balance between moldability and disintegrating property is measured and found to be more than 55°. The fluidity of this crystalline cellulose powder is thus not satisfactory. Particularly when molded under a high striking pressure, the crystalline cellulose disclosed in the above reference can be given a high hardness but has the following problems: the water vapor specific surface area of particles after drying is so small that the conduits in the resulting tablets is decreased to retard the disintegration of the tablets; and in the case of, for example, a recipe in which the proportion of an active ingredient having a low fluidity is high, the coefficient of variation of the weight of the resulting tablets is increased because of the low fluidity to affect the uniformity of the content of a drug.
In addition, JP-A-11-152233 discloses crystalline cellulose having an average polymerization degree of 100-375, a content of particles capable of passing through a 75-μm screen and remaining on a 38-μm screen of 70% or more based on the total weight of the crystalline cellulose, and an average L/D (the ratio of the major axis to the minor axis) value of particles of 2.0 or more. This reference, however, does not describe the angle of repose of the crystalline cellulose disclosed therein. The crystalline cellulose specifically disclosed which is obtained by sieving the crystalline cellulose disclosed in JP-A-6-316535 has problems of worse fluidity and disintegrating property than the crystalline cellulose of JP-A-6-316535 itself. JP-A-50-19917 discloses a process for producing an additive for molding tablets which comprises depolymerizing purified pulp to an average polymerization degree of 450-650 by pretreatment, and subjecting the depolymerization product to mechanical grinding treatment until the apparent tapping specific volume becomes 1.67-2.50 cm3/g and the particle size becomes such a value that 50% or more of the particles pass through a 200-mesh screen. The cellulose powder disclosed in this reference is disadvantageous in that its polymerization degree is so high it exhibits fibrousness, the average L/D value of its particles of 75 μm or less and its apparent specific volume are too large, so that it is poor in disintegrating property and fluidity. The fact that the apparent tapping specific volume of this cellulose powder is small for its apparent specific volume is also a cause for the deterioration of the disintegrating property of tablets obtained by compression.
As described above, no cellulose powder having moldability, fluidity and disintegrating property at the same time with a good balance among them has been known as conventional cellulose powder.
Medicine often has a form of a granular preparation such as granules or fine granules, to which a coating is applied to improve the stability of an active ingredient, adjust the release rate of a drug, mask a taste, or impart enteric properties; or a form of a matrix type granular preparation obtained by granulating a mixture of a coating agent and a drug together with other ingredients. When the granular preparation has a particle size of about 1 mm or less, it is made into capsules in most cases from the viewpoint of ease of handling, but it is preferably made into tablets by compression molding of a mixture of the granular preparation and an excipient, from the viewpoint of cost and ease of taking. However, when granules having a coating film, such as sustained release coated granules, bitter-taste-masked granules, enteric coated granules or the like are tabletted by compression, there is the following problem: the coating film is damaged by compression stress and hence the rate of dissolution and release is increased in mouth, stomach and intestines, so that the exhibition of an expected drug efficacy is not achieved. In order to solve this problem, the following methods have been disclosed. JP-A-53-142520 discloses a method wherein crystalline cellulose is used. JP-A-61-221115 discloses a method wherein crystalline cellulose is used in a proportion of approximately 10-50% based on the amount of tablets. JP-A-3-36089 discloses a method wherein crystalline cellulose having an average particle size of 30 μm or less and a specific surface area of 1.3 m2/g or more is used. JP-A-5-32542 discloses a method wherein crystalline cellulose having a specific surface area of 20 m2/g or more and a porous structure in which the total volume of pores having a diameter of 0.01 μm or more is 0.3 cm3/g or more. JP-A-8-104650 discloses a method wherein a microcrystalline cellulose having an average polymerization degree of 150-220, an apparent specific volume of 4.0-6.0 cm3/g an apparent tapping specific volume of 2.4 cm3/g or more, a specific surface area of less than 20 m2/g, an acetic acid retention of 280% or more, a content of particles of 355 μm or more of less than 5 wt %, a particle size distribution with an average particle size of 30-120 μm, compression characteristics represented by Kawakita's equation wherein the constants a and b are 0.85-0.90 and 0.05-0.10, respectively, and such compression molding characteristics that a cylindrical molded product with a base area of 1 cm2 obtained by compressing 500 mg of the crystalline cellulose at 10 MPa for 10 seconds has a fracture strength in the direction of diameter of 10 kg or more (100 N or more in terms of a fracture strength in SI system of units) and a disintegration time of 100 seconds or less, is used.
The methods disclosed in JP-A-53-142520 and JP-A-61-221115, however, are disadvantageous in that because of the low compression moldability of the microcrystalline cellulose, high compression stress is unavoidably applied in order to attain a practical hardness, so that the damage to the coating film cannot be sufficiently prevented. The method disclosed in JP-A-3-36089 is disadvantageous in that the microcrystalline cellulose has a low fluidity and hence is apt to be separated and segregated from granules during the preparation of tablets. The microcrystalline cellulose disclosed in JP-A-5-32542 is disadvantageous in that it is not practical due to high cost which attributes to the use of an organic solvent for the preparation thereof. In the case where high compression stress cannot be applied, for example, the case where the strength of granules is low, the content of crystalline cellulose should be increased in order to reduce the compression stress. In such a case, the crystalline cellulose disclosed in JP-A-8-104650 is disadvantageous in that the use of the crystalline cellulose is limited, as it makes the disintegration of the resulting tablets very difficult.
Many active ingredients for medicine are often used after being made into fine particles, and have such a low fluidity that they are not easily compression-molded by a direct compression method (a direct striking method). In particular, the larger the amount of the active ingredient for medicine to be added, the more difficult the compression molding. The above JP-A-8-104650 describes that the use of the above-mentioned microcrystalline cellulose, a fluidizing agent and a disintegrating agent for Chinese orthodox medicine powder or crude drug powder ensures enough fluidity to be subjected to a direct tabletting method, and thus makes it possible to produce tablets having an excellent balance between moldability and disintegrating property. However, in the case where the content of an active ingredient for medicine having a low moldability, which is not limited to Chinese orthodox medicine powder or crude drug powder, is increased in a pharmaceutical composition, there is still a problem that sufficient fluidity cannot be attained. Moreover, if the amount of a disintegrating agent is not sufficient, the retardation of disintegration and a decrease of the rate of dissolution occur. Since an active ingredient powder for medicine is poor in compression moldability and cannot give a molded product without the addition of an excipient, a granule compression method is generally adopted in which compression moldability, disintegrating property and fluidity are assured by carrying out a step of granulating the active ingredient for medicine together with an excipient by a well-known wet or dry process, and then the resulting granules are compression-molded. An extra-granulation method is also often adopted as a means for enhancing the effect of the addition of an excipient by adding the excipient outside the granules besides the excipient added inside the granules upon producing the granules. JP-B-5-38732 discloses a crystalline cellulose having an average particle size of 30 μm or less and a specific surface area of 1.3 m2/g or more. JP-A-8-104650 discloses a process for tabletting, using specific crystalline cellulose, by the granule compression method. These crystalline celluloses, however, are disadvantageous in that when compression stress is increased, the disintegration is retarded and the rate of dissolution is decreased.